This invention relates to the treatment of hyperproliferative diseases, such as cancers, in mammals using substituted carboxylic acid derivatives, and substituted derivatives of other acids, of formula I, as defined below. The compounds of formula I are described in J. Med. Chem., 1996, 39, 3897-3907 and U.S. Pat. No. 5,089,514, which issued Feb. 18, 1992, both of which are incorporated herein by reference in their entirety. These references describe compounds of formula I, specifically the substituted carboxylic acid derivatives of formula I, as hypoglycemic agents useful in the treatment of diabetes and related disorders.
A cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype. It has been shown that certain tyrosine kinases may be mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Furthermore, the overexpression of a ligand for a tyrosine kinase receptor may result in an increase in the activation state of the receptor, resulting in proliferation of the tumor cells or endothelial cells. Thus, it is believed that the growth of mammalian cancer cells can be selectively inhibited by reducing tyrosine kinase activity.
Polypeptide growth factors, such as vascular endothelial growth factor (VEGF) having a high affinity to the human kinase insert-domain-containing receptor (KDR) or the murine fetal liver kinase 1 (FLK-1) receptor, have been associated with the proliferation of endothelial cells and more particularly vasculogenesis and angiogenesis. See PCT international application publication number WO 95/21613 (published Aug. 17, 1995). A significant body of evidence has been put forth detailing the importance of VEGF in the formation of new blood vessels (angiogenesis). It has also been noted that new blood vessel formation is crucial in supplying and maintaining the physiological conditions and nutrients necessary for tumor growth and metastasis. It has been shown that both VEGF receptor subtypes appear to be over expressed in proliferating endothelial cells located in near proximity to tumor cells in vivo. At the molecular level, intracellular portions of both FLT-1 and FLK-1 contain functional tyrosine kinase domains. Kinase activities depend on high affinity to, and interaction with, VEGF. Such interaction results in the autophosphorylation of the receptors and ultimately in endothelial cell proliferation. High affinity VEGF binding and the resulting functional effects appear to depend on the presence of specific heparin sulfate proteoglycans (VEGF glyceptor) associated with the extracellular matrix of endothelial cells. This supposition is supported by the ability of exogenous levels of heparin to inhibit VEGF induced endothelial cell proliferation by acting as a sink for secreted VEGF. By inhibiting the binding of VEGF to VEGF glyceptor (GAG), phosphorylation of tyrosine (kinase) is modulated. Agents, such as the compounds of the present invention, which are capable of modulating the KDR/FLK-1 receptor, may be used to treat disorders related to vasculogenesis or angiogenesis. Such disorders include, but are not limited to, diabetes, diabetic retinopathy, hemangioma, glioma, melanoma, Kaposi""s sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
The present invention is directed to a method of treating hyperproliferation diseases in mammals in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a compound of the formula: 
or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein:
R1 is a group having an acidic proton, particularly xe2x80x94COY1 wherein Y1 is hydroxy, (C1-C3)alkoxy, phenoxy, benzyloxy, amino, (C1-C4)alkanoylamino, (C1-C4)alkanesulfonylamino, benzenesulfonylamino, naphthalenesulfonylamino, di[(C1-C4)]aminosulfonylamino or one of the foregoing groups mono- or disubstituted with (C1-C3)alkyl, trifluoromethyl, hydroxy, (C1-C3)alkoxy, fluoro or chloro, or R1 is xe2x80x94SO2H, xe2x80x94PO3H2, 
R2 and R3 are independently selected from hydrogen, (C1-C10)alkyl, phenyl, and a 4 to 10 membered heterocyclic group, which is optionally substituted by one or more R4 groups;
R4 is thienyl, pyridyl, furyl, or pyrimidyl, halogen, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy, optionally substituted with from one to three fluorine atoms, (C3-C10) aryl, phenyl, xe2x80x94(CH2)t phenyl, xe2x80x94(CH2)txe2x80x94(4 to 10 membered heterocyclic group), nitro, cyano, amino, xe2x80x94NH(C1-C6)alkyl, xe2x80x94N((C1-C8)alkyl)2, xe2x80x94S(C1-C8)alkyl, xe2x80x94SO(C1-C8)alkyl, xe2x80x94C(O)(C1-C8)alkyl, xe2x80x94CO(O)(C1-C8)alkyl, wherein said phenyl, aryl or heterocyclic moiety may be optionally substituted with one or two substituents independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, nitro, cyano, amino and trifluoromethyl;
R5 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CH2)t(C6-C10 aryl), or xe2x80x94(CH2)t(4 to 10 membered heterocyclic group), wherein t is an integer from 0 to 5; said alkyl group optionally including 1 or 2 hetero moieties selected from O, S and xe2x80x94N(R6)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R5 groups being optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4 to 10 membered heterocyclic group; one or two carbon atoms in said 4 to 10 membered heterocyclic group of R5 being optionally substituted by an oxo (xe2x95x90O) moiety; R5 groups being optionally substituted by one to five R7 groups;
R6 is H, (C1-C8)alkyl, (C3-CB)cycloalkyl, or a 4 to 10 membered heterocyclic group optionally substituted with (C1-C3)alkyl;
R7 is each independently selected from C1-C10 alkyl, C2-C10alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR8, xe2x80x94C(O)R9, xe2x80x94C(O)OR8, xe2x80x94NR8C(O)OR9, xe2x80x94OC(O)R9, xe2x80x94NR9SO2R8, xe2x80x94SO2NR8R9, xe2x80x94NR9C(O)R8, xe2x80x94C(O)NR8R9, xe2x80x94NR8R9, xe2x80x94S(O)jR10, xe2x80x94SO3H, xe2x80x94NR8(CR9R10)tOR9, xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94SO2(CH2)t(C6-C10aryl), xe2x80x94S(CH2)t(C6-C10aryl), xe2x80x94O(CH2)t(C6-C10aryl), xe2x80x94(CH2)t(4 to 10 membered heterocyclic group), and xe2x80x94(CR9R10)mOR9, said alkyl group optionally containing one or two hetero moieties selected from O, S and xe2x80x94N(R8)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; aryl and heterocyclic moieties of R7 being optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4 to 10 membered heterocyclic group; one or two carbon atoms of the heterocyclic moieties of R7 being optionally substituted by an oxo (xe2x95x90O) moiety; and the alkyl, aryl and heterocyclic moieties of R7 groups being optionally substituted by one to three substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR9SO2R8, xe2x80x94SO2NR8R9, xe2x80x94C(O)R8, xe2x80x94C(O)OR8, xe2x80x94OC(O)R8, xe2x80x94NR9C(O)R8, xe2x80x94C(O)NR8R9, xe2x80x94NR8R9, xe2x80x94(CR9R10)mOR9, xe2x80x94OR8 and R8;
R8 is each independently selected from H, C1-C10 alkyl, xe2x80x94(CH2)t(C6-C10 aryl), and xe2x80x94(CH2)t(4 to 10 membered heterocyclic), said alkyl group optionally including one or two hetero moieties selected from O, S and xe2x80x94N(R6)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R8 groups being optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4 to 10 membered heterocyclic group; the foregoing moieties of R8, with the exception of H, being optionally substituted by one to three substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R9, xe2x80x94C(O)OR9, xe2x80x94CO(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
R9 and R10 are each independently H or C1-C6 alkyl;
X is S, O, NR6, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94 or xe2x80x94Nxe2x95x90CHxe2x80x94;
Y is CH or N;
Z is H, O-allyl, O-phenyl, Oxe2x80x94CH2CH2CH2OH, S-methyl, S-propyl, S-octyl, or S-benzyl;
n is now one or two;
m is an integer ranging from one to five;
r is an integer ranging from one to five, the moiety (CH2)rt optionally including one or more carbon-carbon double or triple bond when r is an integer of from two to five;
t is an integer ranging from zero to five, each moiety (CH2)t optionally including one or more carbon-carbon double or triple bond when t is an integer of from 2 to 5;
s is an integer of from one to five, the moiety (CH2)s optionally including one or more carbon-carbon double or triple bond when s is an integer of from 2 to 5; and
Preferred compounds include those of formula I wherein R1 is xe2x80x94COOH.
Other preferred compounds include those wherein r is zero, R2 is phenyl and R3 is H.
Other preferred compounds are those wherein X is O and Y is N.
Another preferred class of compounds comprises compounds of the formula 
wherein R4, Y and n are as defined for formula I.
Specific preferred compounds of formula II include:
3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methylsulfanyl-propionic acid;
2-Methylsulfanyl-3-[2-(5-methyl-2-m-tolyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-propionic acid;
2-Benzylsulfanyl-3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-propionic acid;
3-[2-(5-Methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-2-octylsulfanyl-propionic acid;
3-[2-(5-Methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-2-propyisulfanyl-propionic acid;
2-Allyloxy-3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-propionic acid;
2-(3-Hydroxy-propoxy)-3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-propionic acid;
3-[2-(5-Methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-propionic acid; and
3-[2-(5-Methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-2-phenoxy-propionic acid.
In one embodiment, the method of the invention relates to the treatment of cancer such as brain, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, lung, renal, gynecological (such as ovarian) or thyroid cancer. In another embodiment, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., benign prostatic hypertropy (BPH)).
The invention also relates to a method for the treatment of a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
The invention also relates to a method of treating pancreatitis or kidney disease in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof.
The invention also relates to a method of preventing blastocyte implantation in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof.
The invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal which comprises administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof. In one embodiment, said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, macular degeneration, hemangioma, glioma, melanoma, Kaposi""s sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
Further, the compounds of the present invention may be used as contraceptives in mammals.
Patients that can be treated with the compounds of formula I and the pharmaceutically acceptable salts and hydrates of said compounds according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis, BPH, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer or cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin""s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphonas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), or neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumors, brain stem gliomas or pituitary adenomas).
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched moieties. It is understood that for cyclic moieties at least three carbon atoms are required in said alkyl group.
The term xe2x80x9calkenylxe2x80x9d, as used herein, unless otherwise indicated, includes monovalent hydrocarbon radicals having at least one carbon-carbon double bond and also having straight, cyclic or branched moieties as provided above in the definition of xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkynylxe2x80x9d, as used herein, unless otherwise indicated, includes monovalent hydrocarbon radicals having at least one carbon-carbon triple bond and also having straight, cyclic or branched moieties as provided above in the definition of xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, unless otherwise indicated, includes O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is as defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term xe2x80x9c4 to 10 membered heterocyclicxe2x80x9d, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the compounds listed above, may be C-attached, S-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula I.
The compounds of formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula I are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Those compounds of the formula I that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and particularly, the sodium and potassium salts. Certain compounds of formula I may have asymmetric centers and therefore exist in different enantiomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof. The compounds of formula I may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
The subject invention also includes isotopically-labeled compounds, and the pharmaceutically acceptable salts thereof, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
This invention also encompasses pharmaceutical compositions containing, and methods of treating diseases related to vasculogenesis or angiogenesis in mammals through administration of prodrugs of, compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of formula I. The amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. The amide and ester moieties may incorporate groups including, but not limited, to ether, amine and carboxylic acid functionalities. Free hydroxy groups may be derivatized using groups including, but not limited to, hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in D. Fleisher, R. Bong, B. H. Stewart, Advanced Drug Delivery Reviews (1996) 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in R. P. Robinson et al., J. Medicinal Chemistry (1996) 39, 10.